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Estradiol Metabolism in Cirrhosis

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Estradiol Metabolism in Cirrhosis Estradiol Metabolism in Cirrhosis BARNETT ZUMOFF, JACK FISHMAN, T. F. GALLAGHER, and LEON HELLMAN From the Division of Neoplastic Medicine and the Institute for Steroid Research, Montefiore Hospital and Medical Center, New York A B S l R A C T Abnormal estrogen metabolism has cirrhosis, too, is characterized by the reciprocal eteln found in cirrhosis after administration of relationship between decreased 2-hydroxylation intravenous tracers of estradiol-3H to 6 patients and increased 16a-hydroxylation previously de- and 23 healthy controls. The major abnormalities scribed in hypothyroidism and male breast cancer. observed involved estrogen metabolites other than However, unlike these latter, the increase of 16a- the 3 "classic" ones, i.e., estrone (El), estradiol hydroxy metabolites was less than the decrease (E2), and estriol (E3). Urinary recovery of of 2-hydroxy metabolites. The data indicate clear- radioactivity was regularly elevated in the patients, cut impairment of 2-hydroxylation, suggestive im- to an average of 71 % of the dose compared to pairment of 16a-hydroxylation, and a definite 51% in Tormals. This is considered to reflect the dlelression of the reaction 16a-hydroxyestrone--> component of in trahep-atic cholestasis in cirrhosis. estriol, the latter finding so far unique to cirrhosis. The per cent (lose recovered as urinary glutco- Demonstration of abnormal peripheral metabolism siduronates (42% ) was normal in cirrhotics in of estrogen in cirrhosis provides a new approach contrast to impaired glucuronidation of cortisol to the origin of the hyperestrogenic syndrome in metabolites in this disease. El and E2 were present this disease. in normial anmouints, and E3 was slightly elevated to 21 % of the extract compared to 14%o in con- INTRODUCTION trols. There were strikingly decreased excretion of 2-hydroxyestronie (3% compared with normal The central role of the liver in the transformation 20'j1 ) anid 2-methoxyestrone (2% compared with of steroids and the well-recognized occurrence of 5'/, ) and(l increase(l excretion of 16a-hydroxy- a hyperestrogenic syndrome in liver disease (2) estroiie (12%1o compare(l with normal 6%). Thus hlave stimulated investigation of estrogen metab- olism in liver disease. The current status has been A preliminary report of this work has been published summarized in a recent review Schedl in abstract form (1). by (3). Address requests for reprints to Dr. Barnett Zumoff, Virtually all the available data have been obtained Division of Neoplastic Medicine, Montefiore Hospital and either by bioassay or by chemical assay methods Medical Center, New York 10467. limited to the 3 "classical" estrogen metabolites,' Recei-ved for publication 30 June 1967 and in revised El (estrone)l E2 (estradiol), and E3 (estriol). formn 17 August 1967. The following trivial namiies have been used for metabolites: estradiol (F2) :' 3"''°'estratriene-3,17,7-diol estrone (El ) 3-hydroxy-"' '3 (10)estratrien- 1 7-one estriol (E3) A""3 1"'estratriene-3,166a,17,8-triol 16-epiestriol (EF3) At"06'0'estratriene-3,16p,17,8-triol l6a-hydroxyestrone ( 16a-01I- El 3,16a-dillydroxy-A"" 35(0)estratrien-17-one 1 6-ketoestradiol ( 16-0-E-l ) 3,1 7,-dillydroxy-Al"3'510estratrien-16-one 2-hydroxyestronle (2-OH-El) 2,3-dihydroxy--A" 51()estratrien-17-one3. 2-methoxyestrone (2-MeO-E1 2-methoxy-3-hydroxy-A1""'50'0)estratrien-17-onq (20 The Journal of Clinical Investigation Volume 47 1968 The inadequacies of both methods have been well METHODS understood by workers in the field. In addition, Five men, aged 39-50, and one woman, aged 37, were studies utilizing chemical methods have been studied. Each patient had typical clinical and laboratory shown to be subject to two serious limitations. findings of cirrhosis (Table I), as well as a long history together have of alcoholism. At the time of study, each patient was hos- First, the three classical metal)olites had a of the urinary pitalized at the Clinical Research Center and had been shown to constitute about 40%o period of rest, adequate diet, and enforced abstinence from estrogens (4). Other identified metabolites, e.g. alcohol. 2-hydroxyestrone, 2-methoxyestrone, 16-epiestriol, Each subject studied received approximately 1 ,uc of 16a-hydroxyestrone and 16-ketoestradiol, make up estradiol-6,7-'H by intravenous injection of a weighed most of the remainder. Studies that do not include amount of a solution of the steroid in freshly redistilled pyrogen-free propylene glycol. A weighed aliquot of these compounds are incomplete and may, on occa- propylene glycol solution from which the individual sion, be misleading. It was found in the present tracer doses were obtained was used for calculation of the study that an analysis restricted to the three clas- administered dose of radioactivity. Complete urine col- sical metabolites would have yielded a quite er- lections as judged from the consistency of creatinine mea- surements were obtained for 3 days after each injection. roneous picture of estrogen metabolism in cir- The specimens were refrigerated immediately after void- rhosis. Second, studies of the "urinary production ing and at all times until the collection was complete. rate" of estradiol have shown discrepancies be- If not processed immediately, and this was done in most tween values determined from different metabolites instances, the entire sample was frozen and kept at - 150C of formation until it was possible to separate the steroid metabolites. (5). This indicates that the pathways The radioactive steroids used were homogeneous by iso- of different estrogen metabolites may include vary- topic dilution analyis. The carrier steroids used were re- ing proportions of multiple precursors, some of crystallized to constant melting point before addition which may never have been effective estrogens. to the extract. Purity of carrier steroids was also checked It appears, therefore, that critical evaluation of by thin-layer chromatography and by infrared spec- trometry. All solvents employed were redistilled and of the fate of biologically active estrogen is best ac- high quality. complished by studies of estradiol biotransforma- In each study the 3 day urine collections were combined tion, with radioactive tracers. Very few studies of and divided into 10, 50, and 40% aliquots, of which the this type have been reported. A preliminary com- last was frozen and retained. A known amount (approxi- munication by Crowell, Ereii, and Preedy (6) mately 30 mg) of carrier 2-hydroxyestrone was added to the 10% aliquot; no carrier was added to the 50%o reported' nornmal estradiol l)roduction in cirrhosis, aliquot. Each was incubated with 300 U of 8-glucuroni- but gave few details concerning the pathways of dase2 per ml of urine at pH 5 with acetate buffer at estrogen metabolism. A preliminary communica- 380C for 5 days. The urine at pH 5 was extracted con- tion by Stoa and Thorsen (7) reported little devia- tinuously with ether for 48 hr. The ether extract was metabolism of washed with 9% sodium bicarbonate solution saturated tion from normal in the estradiol with sodium chloride, with saturated sodium chloride solu- cirrhotic patients. In a somewhat more detailed tion, and finally with a very small amount of water, and preliminary communication, Shaver, Roginsky, the solvent was removed. The residue is designated "glu- and Christy (8) reported evidence that suggested cosiduronate extract." It should be noted that sulfate con- an elevated blood estrogen level and delayed jugates are not hydrolyzed by this procedure although 2-deoxy-2-acetamido-D-glucosides (if present) may be; hepatic estrogen inactivation in cirrhosis. double conjugates with glucuronic and sulfuric acid would In the present study the metabolism of tracer not be cleaved to lipid-soluble compounds. These, there- doses of radioactive estradiol was studied in six fore, would be included as "nonglucosiduronate." patients with cirrhosis and was found to be con- The extract-from the 10% aliquot was used only for sistently abnormal, in total excretion, conjugation, measurement of 2-hydroxyestrone and estradiol. A known amount of estradiol-17,8 approximately equal to the and the relative quantities of metabolites. De- amount of 2-hydroxyestrone was added. The mixture was creased efficiency of certain pathways of peripheral acetylated by standing overnight in pyridine and acetic estradiol metabolism was demonstrated, and there anhydride. Excess reagent was removed under a nitrogen formation of a normally minor stream on a water bath, and the acetates were chromato- was increased with 3: 2 metabolite, 16a-hydroxyestrone. The existence of graphed on 8 g of acid-washed alumina. Elution abnormal peripheral estrogen metabolism in cir- 2p.-Glucuronidase, known as Ketodase, was obtained rhosis provides a new approach to the understand- from Warner-Chilcott Laboratories, a division of Warner- ing of the hyperestrogenic syndrome in this disease. Lambert Pharmaceutical Company, New York. Estradiol Metabolism in Cirrhosis 21 TABLE I Clinical Description of Cirrhotic Pattents Glutamic- Alkaline oxaloacetic plhosphatase Per cent Scrumn transaminase (Bessey- free Dcgree of bilirubin (Karman- Lowry units) cholesterol illness Portacaval (normal Ladue units) (normal Total (normal Subject Age Sex (() 5)* shunt Ascites <0.8) (normal <40) <3.0) cholesterol <34) mg/100 ml mg/100 ml BO 50 M 3 No No 0.3 76 4.2 285 38 NS 42 M 3 No No 1.0 30 4.6 169 39 IN 49 M 1 No No 0.9 36 2.4 235 30 LY 37 F 3 No No 0.3 20 4.2 191 34 HS 39 M 4 Yes No 2.0 59 3.5 230 40 CY 41 M 3 No Yes 2.0 69 3.9 217 40 * 1 = good health; 5 = critically ill. (v/v) benzene-petroleum ether (boiling range 58'-62'C) Since these two metabolites are not separable by routine gave estradiol diacetate, which was recrystallized to con- chromatographic procedures, the amount of 16a-hydroxy- stant specific activity from petroleum ether-acetone.
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